The present disclosure pertains generally to double-stranded oligonucleotides that modulate gene expression for use in research, diagnostics, and/or therapeutics. One method of modulation of gene expression is RNA interference (RNAi). RNAi generally refers to gene silencing involving the introduction of double-stranded RNA (dsRNA) leading to the sequence-specific reduction of targeted endogenous mRNA levels. The reduction of target mRNA can occur by one of several different mechanisms, depending on the sequence of structure of the dsRNA, such as degradation of the target mRNA or transcriptional silencing in which transcription of the mRNA is inhibited. An additional example of modulation of RNA target function by an occupancy-based mechanism is modulation of microRNA function. MicroRNAs are small non-coding RNAs that regulate the expression of protein-coding RNAs. The binding of an RNAi compound to a microRNA prevents that microRNA from binding to its messenger RNA targets, and thus interferes with the function of the microRNA. Regardless of the specific mechanism, this sequence-specificity makes RNAi compounds extremely attractive as tools for target validation and gene functionalization, as well as therapeutics to selectively modulate the expression of genes involved in the pathogenesis of malignancies and other diseases.
DUX4 is a retrogene encoded in each unit of the D4Z4 macrosatellite repeat array. D4Z4 repeats are bi-directionally transcribed in somatic tissues and generate long stretches of RNA and small RNA fragments that may have a role in epigenetic silencing. Inefficient epigenetic repression of DUX4 in skeletal muscle leads to aberrant expression of the DUX4 protein and facioscapulohumeral dystrophy (FSHD) 1 and 2. FSHD1 and 2 patients exhibit progressive, asymmetric muscle weakness, and there is a need for effective treatment for this disease.